Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.

Background. The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far.

Summary: Background and objectives: Both prolactin clearance and production are altered in CKD. In nonrenal populations, emerging evidence suggests that prolactin participates in the atherosclerotic process. Given the elevated cardiovascular risk of CKD, this study examined links between prolactinemia, vascular derangements, and outcomes. Design, setting, participants, & measurements: This observational study was conducted in two cohorts: one with 457 nondialyzed CKD patients (mean age 52±12 years; 229 men) with measurements of flow-mediated dilation (FMD) and carotid intima-media thickness and one with 173 hemodialysis patients (65±12 years; 111 men) with measurements of pulse wave velocity (PWV). Patients were followed for cardiovascular events (n=146, nondialyzed cohort) or death (n=79, hemodialysis cohort). Results: Prolactin levels increased along with reduced kidney function. Prolactin significantly and independently contributed to explain the variance of both FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but not intima-media thickness. In Cox analyses, the risk of cardiovascular events in nondialyzed patients increased by 27% (hazard ratio [HR], 1.27; 95% confidence interval [95% CI], 1.17–1.38) for each 10 ng/ml increment of prolactin. Similarly, the risk for all-cause and cardiovascular mortality in hemodialysis patients increased by 12% (HR, 1.12; 95% CI, 1.06–1.17) and 15% (HR, 1.15; 95% CI, 1.08–1.21), respectively. This was true after multivariate adjustment for confounders and after adjustment within the purported causal pathway (FMD or PWV). Conclusions: Prolactin levels directly associated with endothelial dysfunction/stiffness and with increased risk of cardiovascular events and mortality in two independent cohorts of CKD patients.

Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up. Nonetheless, the exact molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus remain elusive. We hypothesized that defective trafficking of the COL4A3 chain causes a strong intracellular effect on the cell responsible for COL4A3 expression, the podocyte. To this end, we overexpressed normal and mutant COL4A3 chains (G1334E mutation) in human undifferentiated podocytes and tested their effects in various intracellular pathways using a microarray approach. COL4A3 overexpression in the podocyte caused chain retention in the endoplasmic reticulum (ER) that was associated with activation of unfolded protein response (UPR)–related markers of ER stress. Notably, the overexpression of normal or mutant COL4A3 chains differentially activated the UPR pathway. Similar results were observed in a novel knockin mouse carrying the Col4a3-G1332E mutation, which produced a phenotype consistent with AS, and in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation. These results suggest that ER stress arising from defective localization of collagen IV chains in human podocytes contributes to the pathogenesis of TBMN and AS through activation of the UPR, a finding that may pave the way for novel therapeutic interventions for a variety of collagenopathies.

Objectives: Infection is a common cause of death among hemodialysis patients. The study investigated incidence, risk factors, clinical features and outcome of bloodstream infections (BSIs) in haemodialysis patients.